Abnormal microvascular response at the skeletal muscle capillary level may play a pathophysiologic role in the development of insulin resistance and type-2 diabetes mellitus (DM). Under normal circumstances, physiologic hyperinsulinemia increases capillary blood volume which is thought to augment glucose and insulin delivery to skeletal muscle. Impairment in this response may lead to impaired carbohydrate metabolism and insulin resistance. In the initial funding period of this grant, we introduced contrast-enhanced ultrasound (CEU) as a technique to characterize skeletal muscle capillary responses to metabolic stimuli in animal models and in humans. CEU is unique in its ability to rapidly quantify changes in capillary blood volume and velocity separately. Our studies provided important information on the magnitude, timing and mechanisms of capillary recruitment that occurs in response to physiologic hyperinsulinemia, meals, and exercise. We also demonstrated that capillary recruitment in response to physiologic hyperinsulinemia is impaired in obese humans with insulin resistance and rat models of obesity and advanced DM. In order to establish a pathophysiologic role of impaired capillary recruitment, we propose in this grant renewal to study the temporal relation between the development of insulin-resistance and skeletal muscle capillary responses to insulin and exercise in a non-human primate model of insulin resistance produced by high fat diet and activity restriction in adult Rhesus macaques. Specifically, we will determine whether the onset of abnormal skeletal muscle capillary responses to insulin precedes or coincides with the development of insulin resistance and abnormalities in glucose metabolism. We will also test whether the beneficial effect of physical activity and daily exercise on insulin sensitivity correlates with similar salutary effects on capillary responses to metabolic stimuli. In order to determine whether there is a generalized deficit in vascular responses at the onset of insulin resistance, we will also study whether abnormal capillary responses to insulin correlate temporally and in proportion to abnormal capillary responses to other physiologic responses such as exercise, reactive hyperemia, and NO-dependent vasodilation. . We believe that these studies are critical for establishing that abnormal vascular responses play a causative role in insulin resistance and DM and are not simply a consequence of disease. They may also provide the basis investigating new therapeutic strategy aimed at improving glucose utlization through vasoactive agents that exert an effect at the capillary level. PUBLIC HEALTH RELEVANCE: In this proposal, our aim is to determine the contribution of abnormal microvascular responses to during the development of insulin resistance and diabetes mellitus. These studies will be vital not only for understanding the pathophysiology of diabetes, but will also be important for establishing a method to test new treatment strategies or diagnostic strategies for early diabetic risk profiling.